Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.6 (thromboplastin)
13,278 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Infusion of the large volumes of high molecular weight hydroxyethyl starch (HES) has been know to lead to coagulation disorders. Medium molecular starch is considered a safe alternative, even after repeated administration. In 10 patients with cerebrovascular diseases, a 10-day hemodilution was carried out using 10% HES 200/0.62. Initially, a loading dose of 500 ml was administered once over 45-60 min, followed by 500 ml maintenance dose per day for 10 days. Its high intravascular molecular weight (120,000 D) showed that cleavage of the starch is slowed due to the higher degree of substitution. The continuous increase of HES-serum concentration to 27.7 mg/ml gave evidence of a cumulation of poorly degradable molecules. Although this caused a prolonged volume effect, plasma viscosity and erythrocyte aggregation were influenced in an unfavourable way. The negative effects were not evident in their influence on the coagulation system. Under therapy, a significant 42.8% increase (p < 0.01) in activated partial thromboplastin time occurred. Factor VIII:C, von Willebrand ristocetin co-factor and von Willebrand factor antigen dropped during the therapy below the hemostasiological limit of 30% (p < 0.01), and in some patients below 10%. A high degree of substitution, particularly after repeated infusion, leads to a cumulation of large molecules that are difficult to break down and which unfavourably affect rheological and hemostasiological parameters.
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PMID:Increased haemorrhagic risk after repeated infusion of highly substituted medium molecular weight hydroxyethyl starch. 903 38

A 74-year-old man developed a severe bleeding disorder on the basis of acquired Factor VIII (F VIII) inhibitor. Coagulation assays showed a prolonged activated partial thromboplastin time (APTT) with a normal prothrombin time (PT);F VIII level was 0.07 IU and F VIII inhibitor level 8.8 Bethesda units (BU). At least half the cases of acquired haemophilia A are associated with pregnancy, the postpartum period or an underlying malignancy or autoimmune disease. Haemorrhagic diathesis can be severe and life-threatening. Treatment of acute haemorrhages consists of human or porcine factor VIII concentrate, activated prothrombin complex concentrate (FEIBA) or recombinant factor VIIa, depending on the antibody titre. Immunosuppressive therapy is successful in at least 60% of the patients in making the inhibitor disappear. In patients with a spontaneous haemorrhagic diathesis, a thorough medical history should be taken, coagulation assays should be performed and a specialist should be consulted.
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PMID:[Acquired haemophilia A]. 938 Jan 88

Factor VIII (fVIII) functions as a cofactor of factor IXa in the intrinsic pathway of blood coagulation. Its absence or abnormality causes the bleeding disorder hemophilia A. About 23% of hemophiliacs who receive therapeutic fVIII infusions develop antibodies that inhibit its activity. We previously showed by inhibitor neutralization assays that the fVIII A2 and C2 domain polypeptides contain common inhibitor epitopes. Often hemophilic inhibitor plasmas were partially neutralized by C2 and more completely neutralized by fVIII light chain (A3-C1-C2), suggesting the presence of an additional major inhibitor epitope(s) within the A3-C1 domains. In immunoprecipitation assays, 17 of 18 inhibitor IgGs bound to recombinant 35S-A3-C1. Amino acids 1811-1818 of the A3 domain comprise a binding site for factors IX and IXa. Three inhibitor IgGs prevented binding of factor IXa to fVIII light chain, and the binding of each IgG to light chain was competed by A3 peptide 1804-1819. The generation of factor Xa by the fVIIIa/fIXa complex in a chromogenic assay was prevented by these inhibitors. Therefore, we propose that another important mechanism of fVIII inactivation by human inhibitors is the prevention of fVIIIa/fIXa association.
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PMID:Some human inhibitor antibodies interfere with factor VIII binding to factor IX. 963 9

There is no comprehensive study on the stability of coagulation analytes in plasma. We therefore determined the influence of storage time and temperature on prothrombin time, activated partial thromboplastin time, thrombin time, fibrinogen, factors V and VIII, antithrombin III, protein C and S in plasma from 20 healthy subjects and 20 patients receiving heparin therapy. The stability in plasma, defined as the period during which there was a change of less than 10% from the initial value, was 8 hours for activated partial thromboplastin time, 24 hours for prothrombin time, 48 hours for factor V and 7 days for thrombin time, fibrinogen, protein C and antithrombin III in healthy subjects at 6 degrees C. Factor VIII and protein S showed 19 and 12 % reduction in activity, respectively, after 8 hours. In volunteers not treated with heparin therapy, activated partial thromboplastin time was stable for 8 hours; prothrombin time for 48 hours; and thrombin time, fibrinogen and antithrombin III for 7 days with sample storage at room temperature. Factor VIII showed a decrease of 18 % after 8 hours. For patients receiving heparin therapy, the stability of the analytes in plasma stored at 6 degrees C was 8 hours for thrombin time, 24 hours for prothrombin time and activated partial thromboplastin time and 7 days for fibrinogen and antithrombin III. Factors V and VIII showed a decrease of 13 % and 20 % respectively after 8 hours. When the plasma of these patients was stored at room temperature, factor V was stable for 8 hours, and prothrombin time for 24 hours, whereas fibrinogen and antithrombin III remained unchanged for 7 days. Activated partial thromboplastin time showed an increase of 13 %, thrombin time a fall of 16 %, and factor VIII a decrease of 18 % after 8 hours.
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PMID:Influence of time and temperature on coagulation analytes in stored plasma. 974 70

Two patients who presented with active bleeding and were diagnosed with acquired hemophilia A (AHA) are reported herein. One was a 27-year-old woman who experienced spontaneous oozing from an episiotomy wound six days after her second normal delivery. Bleeding became progressively worse, despite treatment with primary sutures and curettage of the uterus at a local hospital. She underwent emergency exploratory laparotomy because of intra-abdominal bleeding, during which perforations of the uterus were discovered. Unremitting bleeding from the surgical wound occurred after surgery. The patient was finally diagnosed with AHA when Factor VIII (FVIII) inhibitor (titer, 19 Bethesda units (BU)/ml) was detected in her plasma. She died of refractory hemorrhaging, despite intensive treatment with Factor IX concentrate infusion and cyclophosphamide therapy. The second patient was a 22-year-old man who sustained spontaneous and recurrent intramuscular hemorrhage in the right thigh for one month. Laboratory studies including complete blood count, biochemical evaluation, coagulation screening and immunologic assays were all within normal limits, except for a prolonged activated partial thromboplastin time. Idiopathic AHA was diagnosed after the detection of plasma FVIII inhibitor with a concentration of 5.9 BU/ml. The patient's coagulopathy was successfully managed with plasma exchange and subsequent treatment with oral prednisolone and cyclophosphamide.
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PMID:Acquired hemophilia A: report of two cases. 979 3

A study of some coagulation factors were carried out in preterm and term infants on the first day of life. Screening coagulation tests--prothrombin time (PT), partial thromboplastin time with kaolin (PTTK) and the concentrations of Factors VIII: C and fibrinogen were determined in 100 normal newborn infants classified into three groups according to their gestational ages: 28 to 30 weeks, 31 to 36 weeks, 37 to 42 weeks. The respective values were compared with those of six-month-old infants as well as adults. The mean values of the screening coagulation tests, PT and PTTK, Factor VIII: C and fibrinogen were significantly different in all the three gestational age groups of nonates when compared with those of six-month-old infants and adult Nigerians. This suggests that a relative hypocagulable state exists among newborn infants and could be responsible for increased bleeding tendencies in these groups of infants. This is the first documented report of coagulation profile in Nigerian neonates, and the range obtained in this study can thus be regarded as standard for healthy Nigerian neonates. The body of data should therefore provide a basis for evaluating newborn noenates with bleeding problems.
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PMID:Coagulation profile in healthy Nigerian neonates. 1045 34

Factor VIII (FVIII) is activated by proteolytic cleavages with thrombin and factor Xa (FXa) in the intrinsic blood coagulation pathway. The anti-C2 monoclonal antibody ESH8, which recognizes residues 2248-2285 and does not inhibit FVIII binding to von Willebrand factor or phospholipid, inhibited FVIII activation by FXa in a clotting assay. Furthermore, analysis by SDS-polyacrylamide gel electrophoresis showed that ESH8 inhibited FXa cleavage in the presence or absence of phospholipid. The light chain (LCh) fragments (both 80 and 72 kDa) and the recombinant C2 domain dose-dependently bound to immobilized anhydro-FXa, a catalytically inactive derivative of FXa in which dehydroalanine replaces the active-site serine. The affinity (K(d)) values for the 80- and 72-kDa LCh fragments and the C2 domain were 55, 51, and 560 nM, respectively. The heavy chain of FVIII did not bind to anhydro-FXa. Similarly, competitive assays using overlapping synthetic peptides corresponding to ESH8 epitopes (residues 2248-2285) demonstrated that a peptide designated EP-2 (residues 2253-2270; TSMYVKEFLISSSQDGHQ) inhibited the binding of the C2 domain or the 72-kDa LCh to anhydro-FXa by more than 95 and 84%, respectively. Our results provide the first evidence for a direct role of the C2 domain in the association between FVIII and FXa.
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PMID:Role of factor VIII C2 domain in factor VIII binding to factor Xa. 1052 97

To assess variations of coagulation factors in women, 123 women were included in a cross-sectional study of the effect of age, ethnic origin, blood group and menstrual cycle on surface induced coagulation time (activated partial thromboplastin time) and plasma levels of Factor VIII clotting assay, von Willebrand factor antigen, von Willebrand factor activity and factor XI. The effect of menstrual cycle was further assessed in a longitudinal study including 39 Caucasian women, 20 of whom were using combined oral contraceptives. Activated partial thromboplastin time was longer in women with blood groups B or O, and plasma levels of factor VIII clotting assay, von Willebrand factor antigen and von Willebrand factor activity were significantly higher in black women. Fibrinogen, von Willebrand factor antigen and von Willebrand factor activity concentrations showed strong cyclic variations with peak values in the luteal phase. This pattern was dampened for von Willebrand factor antigen and von Willebrand factor activity but completely disappeared for fibrinogen with the use of combined oral contraceptives. There was a cyclical pattern for factor VIII clotting assay in pill users, evidence of which was not evident in non-pill users. There were strong associations between the levels of von Willebrand factor antigen and von Willebrand factor activity and age, with levels rising by an average of 0.17 and 0.15 U/ml, respectively, for each 10 year increase in age. In conclusion, there are great inter- and intraindividual variations in coagulation markers in women due to different physiological conditions such as age, ethnicity, blood group and phases of the menstrual cycle. However, there were no significant associations between coagulation markers and weight, alcohol consumption or smoking status.
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PMID:Variations in coagulation factors in women: effects of age, ethnicity, menstrual cycle and combined oral contraceptive. 1059 38

Factor VIII (fVIII) circulates as a heavy chain/light chain (A1-A2-B/ap-A3-C1-C2) heterodimer. The 41-residue light chain activation peptide, ap, is cleaved from fVIII during proteolytic activation by thrombin or factor Xa. We constructed 7 active recombinant hybrid B-domainless human/porcine fVIII molecules that contained combinations of porcine sequence replacements within the A2, ap-A3, and C2 domains. The cross-reactivity of 23 high-titer inhibitory antibodies between human fVIII and the hybrids was inversely related to the degree of porcine substitution. In all plasmas, the substitution of all 3 regions yielded cross-reactivities that were not significantly different from those of porcine fVIII. To differentiate between inhibitor binding to the ap region and the A3 domain, we constructed 2 additional hybrids that contained porcine A2 and C2 domain substitutions and either porcine A3 or porcine ap substitutions. The porcine ap segment was less antigenic than the human ap segment in several plasmas that had activity against the ap-A3 region. This indicates that some inhibitor plasmas contain antibodies directed against the fVIII ap segment in addition to A2, A3, and C2 domain epitopes identified in previous studies. Substitution of porcine sequences within the A2, A3, C2, and ap regions of human fVIII is necessary and sufficient to achieve a maximal reduction in antigenicity relative to porcine fVIII with respect to most inhibitory antibody plasmas. (Blood. 2000;95:564-568)
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PMID:Reduction of the antigenicity of factor VIII toward complex inhibitory antibody plasmas using multiply-substituted hybrid human/porcine factor VIII molecules. 1062 63

Formation of the blood clot is a slow but normal physiological process occurring as a result of the activation of blood coagulation pathways. Nature's guard against unwanted blood clots is the fibrinolytic enzyme system. In healthy people, there is a delicate dynamic balance between blood clot formation and blood clot dissolution. Available evidence suggests that exercise and physical training evoke multiple effects on blood hemostasis in normal healthy subjects and in patients. A single bout of exercise is usually associated with a transient increase in blood coagulation as evidenced by a shortening of activated partial thromboplastin time (APTT) and increased Factor VIII (FVIII). The rise in FVIII is intensity dependent and continues into recovery. The effects of acute exercise on plasma fibrinogen have yielded conflicting results. Thus, the issue of whether exercise-induced blood hypercoagulability in vitro mirrors an in vivo thrombin generation and fibrin formation remains disputable. Exercise-induced enhancement of fibrinolysis has been repeatedly demonstrated using a wide range of exercise protocols incorporating various exercise intensities and durations. Moderate exercise appears to enhance blood fibrinolytic activity without a concomitant activation of blood coagulation mechanisms, whereas, very heavy exercise induces simultaneous activation of blood fibrinolysis and coagulation. The increase in fibrinolysis is due to a rise in tissue-type plasminogen activator (tPA) and decrease in plasminogen activator inhibitor (PAI). The mechanism of exercise-induced hyperfibrinolysis is poorly understood, and the physiological utility of such activation remains unresolved. Strenuous exercise elicits a transient increase in platelet count, but there are conflicting results concerning the effect of exercise on platelet aggregation and activation. Few comprehensive studies exist concerning the influence of exercise training on blood hemostasis, making future investigation necessary to identify whether there are favorable effects of exercise training on blood coagulation, fibrinolysis, and platelet functions.
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PMID:Blood hemostasis in exercise and training. 1079 81


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